Living beings on the Earth have a mechanism, called a biological clock, for a circadian rhythm tuned to a 24-hour environmental cycle from the daytime to the nighttime, such as a light-dark cycle, occurring as the Earth revolves on its own axis. The biological clock is controlled by the hypothalamic suprachiasmatic nucleus of the brain. We have the circadian rhythm of sleep-wakefulness and eating behavior attributed to the biological clock.
The circadian rhythm is observed not only in sleep and diet, but also in most of the body temperature, blood pressure, heart beat, and internal secretion. Understanding the circadian rhythms of the autonomic nervous system, endocrine system, hemodynamics, etc and keeping them normal are considered important to the treatment and prevention of cardiovascular diseases. In modern society, artificial and irregular lives due to work shifts, long distance jet flights, aging of the society, diverse life styles, and so on are becoming routine. In this modern society, there are rapid increases in various diseases attributed to biorhythm disorders, including circadian rhythm-associated sleep disorder. Effective therapeutic action against such diseases is urgently needed. A patient with desynchronosis syndrome (time zone fatigue) due to disturbance of the circadian rhythm falls into insomnia at night, and suffers from a sleep attack during the daytime. The patient is also annoyed by headache, tinnitus, palpitation, nausea, abdominal pain, or diarrhea, and presents with symptoms of decline in judgment and decrease in concentration. Draw-back sleep phase syndrome (DSPS) shows the highest morbidity rate during puberty (Diagnostic Classification Steering Committee, Thorpy M. J.: International Classification of Sleep Disorders: Diagnostic and Coding Manual., American Sleep Disorders Association, Rochester. 1990). Such circadian rhythm-associated sleep disorder among young people makes social adaptation difficult, and hinders the patients from exhibiting their abilities (Kajimura et al.: The Japanese Journal of Clinical Medicine, Vol. 56, No. 2, p. 404, 1998).
Among methods for regulating the disturbance of the circadian rhythm producing such symptoms are psychotherapeutic approaches, non-pharmacotherapies, and pharmacotherapies. The non-pharmacotherapies include irradiation with high illuminance light, which nowadays is actively used for treatment of seasonal affective disorder and circadian rhythmical sleep disorder. For pharmacotherapies, vitamin B12, benzodiazepine hypnotics, etc. are used, but they do not take effect without fail, and established pharmacotherapy is expected. Compared with the hitherto predominant barbiturate or non-barbiturate hypnotics, benzodiazepine hypnotics minimally cause drug tolerance or dependence, and have relatively high safety. However, the benzodiazepine hypnotics are known to produce adverse reactions, such as muscle relaxant action, carry-over effect, and amnestic action, and their use requires due care. That is, there are currently not any excellent compounds which are safe, effective and possessive of a circadian rhythm normalizing action.
Melatonin is expected as a new compound for regulating the circadian rhythm. Melatonin is a hormone mainly produced by the pineal body, and its production shows marked diurnal fluctuations. Its amount produced in the nighttime reaches as large as 50 to 100 times that during the daytime.
When the nocturnal secretion of melatonin is suppressed by the administration of a β-blocker, there occur sleep-wakefulness rhythm disorders, for example, a low quality sleep such as increased midway wakening at night (Brismar et al.: Acta. Med. Scand., 223, p. 525, 1988) and a decreased wakefulness level during the daytime (Dimenas et al.: J. Clin. Pharmacol., 30, s103, 1990). Behind sleep disorder in elderly people lies a decrease in melatonin secretion, and melatonin replacement therapy is considered effective for this disorder (Garfinkel et al.: Lancet, 346, p. 541, 1995). Of aged persons with decreased physiological section of melatonin, those who can sleep well have a large amount of melatonin secreted (Haimov et al.: Sleep. 18, p. 598, 1995). Based on these facts, endogenous melatonin is regarded as a physiological hypnotic substance which takes part in the regulation of the sleep-wakefulness rhythm.
Concerning the hypnotic action of exogenous melatonin, varieties of results have been reported. A report says that the administration of melatonin resulted in upgrading of sleep, such as shortening of hypnagogic latency, decrease in halfway waking, or improvement of insomnia (Zhdanova et al.: Clin. Pharmacol. Ther., 57, p. 552, 1995). On the other hand, there is a report which denies the sleep regulating effect or the sleep disorder improving effect of melatonin (James et al.: Neuropsychopharmacology, 3, p. 19, 1990).
As one of the reasons why these contradictory results were obtained, dosing time dependency has been indicated (Mishima: The Japanese Journal of Clinical Medicine, Vol. 56, No. 2, p. 302, 1998). Another reason may be the fact that melatonin is easily oxidized. In vivo melatonin is known to be metabolized and deactivated by the oxidative ring cleavage reaction of the indole ring by indoleamine-2,3-dioxygenase in the presence of superoxide anions (Hayaishi: J. Biochem., 79, p. 13, 1976). Thus, this reaction easily proceeds in aged persons in whom, or under stress under which, an active oxygen or radical concentration, a cause for occurrence of superoxide anions, is said to be high. Eventually, the concentration of melatonin may lower, making regulation of sleep difficult.
As discussed above, melatonin is clearly a factor involved in the regulation of the circadian rhythm, but much remains to be solved for the full performance of its therapeutic effect. Accordingly, if a circadian rhythm normalizing action can be found in other naturally occurring compounds, their value is very high for use in the prevention of sleep disorder and its associated various diseases. If a compound capable of raising the bioavailability of endogenous melatonin and exogenous melatonin safely and effectively is obtained from a natural substance, its value in use is extremely high.
Astaxanthin is a red carotenoid pigment seen in aquatic animals such as crustaceans or fish, and microorganisms. Astaxanthin has been used as a body color improver for fish, or as an additive for improvement of the color tone of domestic animals (Japanese Unexamined Patent Publication No. 206342/82, Japanese Unexamined Patent Publication No. 54647/85, and Japanese Unexamined Patent Publication No. 63552/92). The antioxidant action of astaxanthin has been demonstrated to be more potent than that of α-tocopherol, so that astaxanthin is expected to find use as an anti-oxidizing agent, a health food, a cosmetic, and a drug, in addition to application as a natural pigment (Eiji Yamashita: Foods and Development, vol. 27, No. 3, p. 38, 1992). Recently, it has been reported that astaxanthin, administered at a dose 1/100 the dose of α-tocopherol, can suppress increases in lipid peroxides in the brain caused by irradiation with 60Co (Nishigaki et al.: J. Clin. Biochem. Nutr., 16, p. 161, 1994).
However, it has not been known that astaxanthin has the action of normalizing the circadian rhythm, and is effective for preventing or alleviating sleep disorder and various diseases due to disturbance of the circadian rhythm. Nor is astaxanthin known to enhance the circadian rhythm regulating action of melatonin. Furthermore, it has not been known thus far to use astaxanthin as a food or beverage, a food additive, or an active ingredient of a drug, intended for a circadian rhythm normalizing effect and a hypnotic action.